Digestive System Diseases

All Conditions

Symptoms and General Pathology

Neoplasms

Liver Diseases

Liver Cirrhosis

Liver Neoplasms

Hepatic Insufficiency

Liver Failure

Gastrointestinal Diseases

Fibrosis

Gastrointestinal Neoplasms

Digestive System Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Anti-Infective Agents

Everolimus

Tacrolimus

Liver Extracts

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Standard immunosuppression protocol with Tacrolimus, maintaining trough levels between 6 and 12 ng/ml in the first month, in association with steroids (20 mg/day with subsequent weaning within 3 months after transplantation).

Administration of Everolimus in association with Tacrolimus and steroids.

Administration of Everolimus within 24 hours from the time of randomization (7 days from the time of transplantation) in association with Tacrolimus and steroids. The first dose level of the trough will be performed at day 7 after initiation of therapy. After the reaching an Everolimus trough level of \>5ng/ml (final target 6-12 ng/ml), there will be a gradual weaning of tacrolimus (bringing Tacrolimus blood levels \<5 ng/ml) with discontinuation of Tacrolimus within 30 days after transplantation when possible.

Umberto Cillo, MD

Laura Saracino, MSc

Michele Colledan, MD

Vittorio Corno, MD

Giorgio Rossi, MD

Paolo Reggiani, MD

Luciano De Carlis, MD

Jacopo Mangoni, MD

Laura Saracino, MBS

Giacomo Zanus, MD

Daniele Neri, MD

Patrizia Boccagni, MD

Francesco D'Amico, MD

Enrico Gringeri, MD

Alessandro Vitale, MD

Pasquale Bonsignore, MD

Paolo Feltracco, MD

Dino Sgarabotto, MD

Roberto Marchini, MD

Angelica Magrofuoco, CCTC

Salvatore Agnes, MD

Erida Nure, MD

Mauro Salizzoni, MD

Francesco Lupo, MD

Fabio Bresàdola, MD

Umberto Baccarani, MD

Safety and Efficacy of Everolimus in adult de novo liver transplant recipients.

This prospective study was designed to evaluate the feasibility and effectiveness of the use of Everolimus in the minimization and possible suspension of calcineurin inhibitors in adult liver transplant patients. The study will take into account a control group (standard immunosuppression with tacrolimus and steroids) after induction with anti-IL2 Antibodies.

Everolimus in de Novo Liver Transplantation: a Multicentre Randomized Study

Terapia Con Everolimus Nel Trapianto de Novo di Fegato: Uno Studio Multicentrico Randomizzato

Patients not requiring calcineurin inhibitors (CNI)

Impact of therapy on renal function, evaluated by creatinine clearance according to the Modification of Diet in Renal Disease (MDRD) Study.

Evaluation of common post Liver Transplantation Adverse Events:

wound healing, bone marrow depression, hyperlipidemia, proteinuria, diabetes mellitus, diagnosed hypertension, infections, levels of HCV.

Azienda Ospedaliera di Padova

Director of the Hepatobiliary Surgery and Liver Transplantation Unit

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Lymphosarcoma

Michel MARTY, MD

About 1500 solid organs transplants are performed each year in the Paris agglomeration.

Cancer risk in the transplanted is about three times higher than in a population of the same age without any organ transplant. Thus cancer is an important problem for organ transplant.

These cancers can be related to many factors :

* Post-transplant cancers are due in part to the non specific immunosuppression, which leads to oncogenic viruses replication, and then produces virus inducted cancers (as lymphoma due to EBV virus).
* Post-transplant cancers can also be due to the carcinogenic factors of the immunosuppressive drugs (as cyclosporine or tacrolimus, which can cause the appearance of metastases). However, a new type of immunosuppressive drugs (mTOR inhibitors) appear to have anti-cancer properties.
* Post-transplant cancers which are not virus-inducted can be relied to genetic factors of the transplanted patient and/or the transplant donor.

There are 4 axes in this study :

* Axis 1 : Epidemiological, clinical and biological study of the incident cancers in transplanted patients.
* Axis 2 : Qualitative and quantitative immunological study of lymphocyte cells by the transplanted patient (determine their characteristics when a cancer appears).
* Axis 3 : Pathological and genetic study of the post-transplant cancer cells (see if the cancer is caused by the donor or the recipient). Creation of a biobank.
* Axis 4 : Pharmacogenetic study of the immunosuppressive drugs (determine the impact of patient genetic variability on tolerance and efficiency of the immunosuppressive drugs).

This is an observational and comparative study (2 control patients are recruited for each 1 case patient).

A case patient is a patient who has developed a cancer after his/her transplant.

A control patient is a patient who has not developed a cancer after his/her transplant.

These 2 groups will be matched according to specific inclusion criteria.

Study of Cancers After Solid Organs Transplants

Epidemiological, Immunological, Pathological and Pharmacogenetic Study of Cancers Occuring After Solid Organs Transplants

CANCEROPOLE Ile-de-France

Assistance Publique - Hôpitaux de Paris

National cohort = 85,410 solid organ transplant recipients receiving their transplant between January 1st 1985 to December 31st 2015

Adnan Sharif, MD

Adnan Sharif

Cancer remains a major cause of morbidity and mortality post solid organ transplantation. While mortality from the other leading causes of death post-transplantation (e.g. cardiovascular disease and infection) is declining, mortality from cancer post-transplantation is increasing. This is due to both general and transplant-specific risk factors that combine to increase risk for cancer compared to the general population. However, there is a shortage of research exploring cancer epidemiology post solid organ transplantation in the UK. This is essential to guide clinicians and for counselling patients regarding expectations and outcomes after developing cancer post-transplantation. This is especially important as the aetiology, pathophysiology and outcomes of cancer post-transplantation may differ from the general population.

Available data registries in the UK separately contain valuable cancer and transplant-specific data that can be combined to explore cancer epidemiology post-transplantation more comprehensively, which can be directly translated into patient benefit by utilizing transplant-specific data (rather than translating from general population or non-UK patient demographics).

The purpose of this project is to combine existing data resources to link up the complete patient journey for solid organ transplant recipients nationally and focus on the entire spectrum of cancer from incidence to mortality.

Solid organ transplantation is associated with an increased incidence of cancer versus the general population, and broadly on par with comparable immune deficiency states such as HIV/AIDS. The aetiology of cancer post-transplantation is primarily due to the burden of immunosuppression that is compulsory for all transplant patients to prevent allograft rejection. Skewed standardised incidence ratios are observed for cancer post-transplantation compared to the general population, with preponderance for cancers with a strong viral component. The literature on cancer-related mortality after transplantation is scarce, but again disparate mortality risk has been documented comparing solid organ transplant recipients to the general population.

There is a shortage of UK-specific data to guide transplant clinicians on how best to deal with cancer. This is important as countries differ with regards to ethnic demographics and post-transplant immunosuppression protocols, both of which are important confounders to translate data from other transplant cohorts. Collett and colleagues have previously published registry data of cancer incidence in British transplant recipients (by linking UK Transplant Registry to various national cancer registries) for a cohort transplanted between 1980 and 2007. They found similarities but also important differences between cancer incidence in a British solid organ recipient cohort versus registry data from Sweden, Finland, Canada and the United States. Importantly, the relevance of this data to the contemporary solid organ transplant cohort is unclear, as immunosuppression protocols have evolved since 2007 to a predominantly tacrolimus-based regimen since publication of the SYMPHONY study in 2007. No subsequent analysis has been done to determine the impact of tacrolimus introduction into cancer occurrence post-transplantation in the UK.

Previous work has analysed cancer-related mortality in the UK, providing data on site of cancer-related mortality and stratifying analysis along demographic factors such as age, gender and/or ethnicity that are relevant to the British population. This analysis linked two different national data resources from the study by Collett and colleagues - Hospital Episode Statistics and the Office for National Statistics. It demonstrated the crude cancer-related mortality rate in England (between 2001 and 2012) was 361 cancer-related deaths per 100,000 person years (compared to 424 and 416 for cardiovascular- and infection-related deaths respectively). Of note, cancer-related mortality within the first year post kidney transplantation (7.4%) has been shown to rise in incidence with increasing time post-transplantation (22.0% beyond the first year post kidney transplantation and second leading cause of death).

This previous work has identified the strengths and limitations of utilising such data resources. One of the major limitations with registry data is the absence of important and relevant information that can confound the data, which can be overcome by linking data between registries. For example, previous analyses identified kidney cancer accounted for over half of all cancer-related mortality for kidney transplant recipients with a history of pre-transplant cancer. However, the limitation of that data was the inability to probe this association further for a number of important issues; 1) location of kidney cancer (whether native or transplant kidney), 2) whether pre-transplant cancer was kidney-related, and 3) time on dialysis pre-transplant (which is a strong risk factor for acquired cystic renal disease and malignant transformation). While this information was unavailable in isolated data sets, such information is contained within other national data resources and could be combined by data linkage to create a broad and comprehensive epidemiological resource.

Data or record linkage has been defined as "a process of pairing records from two files and trying to select the pairs that belong to the same entity." Cancer data is not routinely collated by transplant centers and there is no robust mechanism to explore cancer epidemiology data post solid organ transplantation through the UK Transplant Registry. However, linking information to other existing data registry resources will facilitate such analysis. This is an under-researched area within both transplant and cancer communities, but increasingly important due to the increasing incidence and prevalence of cancer post solid organ transplantation.

Epidemiology of Cancer After Solid Organ Transplantation - EpCOT Study

To compare observed and expected risks of specific causes of deaths, in particular cancer-related death, by linking the UKTR with the national death registry to obtain underlying causes of death and determine factors related to increased risk of specific causes of death post-transplantation. General population mortality rates will be used to calculate expected number of deaths from specific causes and identify subgroups of post-transplant patients (e.g. age, sex, transplant centre, organ type, etc.) at excess risk compared with expected risk.

Investigate survival and causes of death after cancer in post-transplant patients versus individuals from the general population with a similar de novo cancer of the same age, sex, and calendar year of diagnosis.

Compare observed and expected risks of specific cancer types post-transplantation by linking the UKTR with the national cancer registry to obtain observed numbers of cancers and determine factors related to increased risk of specific types of cancer. General population cancer incidence rates will be used to calculate expected numbers of cancers of specific type and identify subgroups of post-transplant patients at excess risk of specific cancers compared with expected.

Estimate risk of morbidity requiring hospitalisation both generally and that associated with development of post-transplantation cancer by linking the UKTR with Hospital Episode Statistics (HES). Risk of hospital admissions and procedures (e.g. surgery) for specific morbidities will be investigated. We will calculate expected risks for specific conditions requiring hospitalisation, enabling identification of specific subgroups of post-transplant patients at excess risk compared with expected.

Machine learning utilising patient level data from linked registries to risk stratify solid organ transplant recipients at risk for cancer

University Hospital Birmingham NHS Foundation Trust

Consultant Nephrologist

Heart and Blood Diseases

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Multiple Myeloma

Neoplasms, Plasma Cell

COVID-19

Leukemia

Leukemia, Lymphoid

Lymphoma, Non-Hodgkin

Acquired Immunodeficiency Syndrome

HIV Infections

Leukemia, Lymphocytic, Chronic, B-Cell

Pneumonia

Pneumonia, Viral

Communicable Diseases

Respiratory Tract Infections

Virus Diseases

Coronavirus Infections

Coronaviridae Infections

Nidovirales Infections

RNA Virus Infections

Lung Diseases

Respiratory Tract Diseases

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Lymphatic Diseases

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Gastrointestinal Agents

Vaccines

Immunomodulating Agents

Pancrelipase

Pancreatin

Eligible participants living with HIV will be randomised 1:1:1 to receive a one or two doses of bivalent COVID-19 vaccine:

1. Moderna bivalent COVID-19 vaccine, SPIKEVAX BIVALENT ORIGINAL/OMICRON BA.4-5 (elasomeran/davesomeran); 25 micrograms of imelasomeran that targets the Omicron variant BA.4-5, and 25 micrograms of elasomeran that targets the ancestral strain of SARSCoV-2.
2. Pfizer bivalent COVID-19 vaccine, COMIRNATY ORIGINAL/OMICRON BA.4-5 (tozinameran/famtozinameran); 15 µg of tozinameran and 15 µg of famtozinameran.
3. TBC

Eligible participants who have previously received at least one solid organ transplant, including kidney, pancreas, liver, heart, lung, or any combination of these organs at least 6 weeks prior and without episodes of severe rejection requiring T- or B-cell depleting agents in the prior 3 months, will be randomised 1:1:1 to receive a one or two doses of bivalent COVID-19 vaccine:

1. Moderna bivalent COVID-19 vaccine, SPIKEVAX BIVALENT ORIGINAL/OMICRON BA.4-5 (elasomeran/davesomeran); 25 micrograms of imelasomeran that targets the Omicron variant BA.4-5, and 25 micrograms of elasomeran that targets the ancestral strain of SARSCoV-2.
2. Pfizer bivalent COVID-19 vaccine, COMIRNATY ORIGINAL/OMICRON BA.4-5 (tozinameran/famtozinameran); 15 µg of tozinameran and 15 µg of famtozinameran.
3. TBC

Undergoing chemotherapy, immunotherapy and/or targeted therapy, or completed in the last 2 years for chronic lymphocytic leukemia, multiple myeloma or non-Hodgkin lymphoma will be randomised 1:1:1 to receive a one or two doses of bivalent COVID-19 vaccine:

1. Moderna bivalent COVID-19 vaccine, SPIKEVAX BIVALENT ORIGINAL/OMICRON BA.4-5 (elasomeran/davesomeran); 25 micrograms of imelasomeran that targets the Omicron variant BA.4-5, and 25 micrograms of elasomeran that targets the ancestral strain of SARSCoV-2.
2. Pfizer bivalent COVID-19 vaccine, COMIRNATY ORIGINAL/OMICRON BA.4-5 (tozinameran/famtozinameran); 15 µg of tozinameran and 15 µg of famtozinameran.
3. TBC

One or Two doses three months apart, per manufacturer's recommendations.

Pfizer Bivalent COVID-19 Vaccine

Moderna Bivalent mRNA vaccine

Michelle Hagenauer

Janine Roney, MPH RN BHSc

James H McMahon, MBBS PhD

Despite the greater risk of adverse COVID-19 outcomes, antibody and cell-mediated immune responses to COVID-19 vaccines vary amongst immunocompromised (IC) people and are poorly defined. IC hosts were largely excluded from the COVID-19 vaccine registration trials, though many countries recommend additional and booster doses of vaccination in this group.

BOOST-IC is an adaptive randomised clinical trial (RCT) to assess the immunogenicity and safety of additional COVID-19 vaccine doses in immunocompromised (IC) people, including people with HIV, solid organ transplants (SOT) recipients or those with haematological malignancies. Briefly, the study aims to generate high-quality evidence on the immunogenicity and safety of alternative COVID-19 booster strategies against SARS-CoV-2 for IC people in Australia.

Despite the greater risk of adverse COVID-19 outcomes, antibody and cell-mediated immune responses to COVID-19 vaccines vary amongst immunocompromised (IC) people and are poorly defined. IC hosts were largely excluded from the COVID-19 vaccine registration trials, though many countries recommend additional and booster doses of vaccination in this group. However, data are heterogeneous, in part due the variable nature of immunodeficiencies in IC groups and non-standardised outcome measures used in studies.

BOOST-IC is an adaptive randomised clinical trial (RCT) to assess the immunogenicity and safety of additional bivalent COVID-19 vaccine doses in immunocompromised (IC) people, including people with HIV, solid organ transplants (SOT) recipients or those with haematological malignancies. Briefly, the study aims to generate high-quality evidence on the immunogenicity and safety of alternative COVID-19 booster strategies against SARS-CoV-2 for IC people in Australia.

To do this, participants who have previously completed 3- to 6-doses of Australian TGA approved COVID-19 vaccines (BA.4/5 Moderna and Pfizer vaccines) will be randomised 1:1 to receive either one or two doses of a bivalent COVID-19 vaccine, as these become available in Australia. And additional arm can be added if an additional suitable vaccine becomes available. Namely, patients will be randomised to receive either one or two doses of bivalent Moderna or Pfizer COVID-19 vaccine. As additional bivalent vaccines become available in Australia, these will be included in the trial, as additional arms. The trial can incorporate up to three arms at one time.

Patients will be followed up for 455 days post randomisation. Specific study questions pertain to:

* examining how additional doses of COVID-19 vaccine/s affect correlates of protective immunity
* examining the safety of additional doses of COVID-19 vaccine/s
* characterising the humoral and cellular immune responses to COVID-19 vaccination receiving 1 or 2 booster doses of COVID-19 vaccine/s

Study participants who have received three to six doses of Australian TGA approved COVID-19 vaccine will be randomised into one of up to three groups, who will be administered either one or two homologous doses of bivalent COVID-19 vaccines, e.g. bivalent Moderna mRNA vaccine OR bivalent Pfizer mRNA vaccine, using a central computer-generated random allocation algorithm, with random block sizes of 3 or 6.

Randomisation will be stratified by:

- Study subgroup (HIV, solid organ transplant, haematological malignancy)

Both study participants and investigators will be blinded to treatment allocation. Individual assignments will be delivered securely and confidentially to the identified site personnel administering the vaccines via a web-based portal.

Bringing Optimised COVID-19 Vaccine Schedules To ImmunoCompromised Populations (BOOST-IC): an Adaptive Randomised Controlled Clinical Trial

geometric mean concentration (GMC) of anti-spike SARS-CoV-2 IgG (AU/ml)

The geometric mean concentration (GMC) (AU/ml) of anti-spike SARS-CoV-2 IgG antibody against SARS-CoV-2 6- and 12-months after completion of trial vaccine/s

The proportion of participants seronegative to SARS-CoV-2 IgG becoming seropositive 1-, 6- and 12-months after completion of trial vaccine/s

Proportion of participants with SARS-CoV-2 neutralising antibody response in each group after 1-, 6- and 12-months post completion of trial vaccine/s, with response defined as either 4-fold rise in the neutralising antibody titre for those with detectable neutralising antibodies at baseline, OR Detectable neutralisation in those with no detectable neutralising antibodies at baseline

Subset analysis and polyfunctionality (number, and concentration of effector cytokines) of SARS-CoV-2 specific T-cell responses at 1-, 6- and 12-months post completion of trial vaccine/s in a subset of participants.

Magnitude of SARS-CoV-2 specific T-cell responses at 1-, 6- and 12-months post completion of trial vaccine/s in a subset of participants

Local and systemic reactions assessed by questionnaire on Day 1,2,3,4,5,6 and 7 after randomisation.

Solicited and unsolicited adverse events following immunisation (AEFI) up to Day 28.

Hospitalisation resulting from adverse events following immunisation (AEFI) up to Day 28.

Proportion with solicited and unsolicited adverse events following immunisation (AEFI) up to Day 28.

Proportion of participants with hospitalisation resulting from adverse events following immunisation (AEFI) up to Day 28.

Proportion of patients with PCR-confirmed OR rapid antigen test (RAT) positive SARS-CoV-2 infection in participants up to 12-months post completion of trial vaccine/s

Proportion of participants with PCR-confirmed OR rapid antigen test (RAT) positive SARS-CoV-2 infection requiring attendance at a medical facility for assessment and/or hospital admission up to 12-months post completion of trial vaccine/s

Proportion of participants experiencing mortality due to i) any cause and ii) SARS-CoV-2 infection up to 12-months post completion of trial vaccine/s

Proportion of participants needing oxygen therapy and/or ventilatory support due to SARS-CoV-2 infection up to 12-months post completion of trial vaccine/s Need for ICU care due to SARS-CoV-2 infection up to 12-months post completion of trial vaccine/s

Proportion of Participants with need for ICU care due to SARS-CoV-2 infection up to 12-months post completion of trial vaccine/s

Quality of life estimates (using EQ-5D-5L survey) at 1-, 6- and 12-months post completion of trial vaccine/s

Proportion of participants with healthcare utilisation including outpatient pharmaceutical and medical service use and inpatient hospital admissions related to COVID-19 or study vaccines up to 12-months post completion of trial vaccine/s

Proportion of participants with healthcare utilisation including outpatient pharmaceutical and medical service use and inpatient hospital admissions

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Everolimus in de Novo Liver Transplantation: a Multicentre Randomized Study	NCT01423708	Liver Failure Liver Diseases Liver Cirrhosis Liver Neoplasms	Everolimus	18 Years - 70 Years	Azienda Ospedaliera di Padova
Study of Cancers After Solid Organs Transplants	NCT00948883	Cancer Organ Transplan...		18 Years -	Assistance Publique - Hôpitaux de Paris
Epidemiology of Cancer After Solid Organ Transplantation - EpCOT Study	NCT02991105	Malignancy		-	University Hospital Birmingham NHS Foundation Trust
Study of Cancers After Solid Organs Transplants	NCT00948883	Cancer Organ Transplan...		18 Years -	Assistance Publique - Hôpitaux de Paris
Everolimus in de Novo Liver Transplantation: a Multicentre Randomized Study	NCT01423708	Liver Failure Liver Diseases Liver Cirrhosis Liver Neoplasms	Everolimus	18 Years - 70 Years	Azienda Ospedaliera di Padova
Everolimus in de Novo Liver Transplantation: a Multicentre Randomized Study	NCT01423708	Liver Failure Liver Diseases Liver Cirrhosis Liver Neoplasms	Everolimus	18 Years - 70 Years	Azienda Ospedaliera di Padova
Bringing Optimised COVID-19 Vaccine Schedules To ImmunoCompromised Populations (BOOST-IC): an Adaptive Randomised Controlled Clinical Trial	NCT05556720	HIV Organ Transplan... Lymphoma, Non-H... Chronic Lymphoc... Multiple Myelom... COVID-19 Vaccin...	Pfizer Bivalent... Moderna Bivalen...	16 Years -	Bayside Health

Spots Global Cancer Trial Database for organ transplantation